Abstract
In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very-low-density-lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1-stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver-specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo-secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell-induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.
Highlights
Cancer-induced cachexia describes a multi-factorial disease condition characterized by massive loss of adipose tissue and skeletal muscle mass and is believed to be responsible for up to (1) Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, Heidelberg, Germany (2) Dept. of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany yThese authors contributed to this work.30% of cancer-related deaths in humans (Fearon et al, 2012)
Our study identifies TSC22D4 as a cachexia-inducible regulator of hepatic VLDL secretion and a molecular determinant of circulating TG levels, associated with a regulatory function in the control of lipogenic gene expression in the liver
We demonstrate that the provision of systemic energy substrates through the liver is greatly impaired in the tumour-bearing condition, mediated via the inhibition of hepatic VLDL lipid secretion
Summary
Cancer-induced cachexia describes a multi-factorial disease condition characterized by massive loss of adipose tissue and skeletal muscle mass and is believed to be responsible for up to (1) Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, Heidelberg, Germany (2) Dept. of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany yThese authors contributed to this work.30% of cancer-related deaths in humans (Fearon et al, 2012). Cancer-induced cachexia describes a multi-factorial disease condition characterized by massive loss of adipose tissue and skeletal muscle mass and is believed to be responsible for up to (1) Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, Heidelberg, Germany (2) Dept. Whereas cancer cachexia has traditionally been seen as a tumour-initiated event that eventually deprives host energy resources to feed tumour growth (Theologides, 1979), more recent studies highlight the role of cachectic metabolism as an integrative, global response to noxious stimuli, including tumours and septic or traumatic conditions (Fearon et al, 2012).
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